Many renal disorders, including acute and chronic kidney disease, common genetic diseases such as autosomal dominant polycystic kidney disease (ADPKD), renal cell carcinoma, glomerulonephritis and other pathological conditions, lead to kidney damage or loss. In the United States, approximately one person in five reaching 65 years of age will undergo organ-replacement during their remaining life span. It is predicted over 2 million patients will suffer from end-stage renal disease by 2010 [2]. Approximately 58,000 patients in the United States and 300 patients in New Mexico are currently on the waiting list for a kidney transplant, with some waiting for several years before an appropriate donor can be found. Substantial fractions of patients (12-17%) on the waiting list are designated as “most-difficult-to-transplant.” Despite the advances in kidney transplantation, a significant shortage of donor organs severely limits treatment for these patients and requires many to remain on dialysis for extended periods of time. The quest for alternate organ restoration methods has resulted in rapid progression of new approaches, such as therapeutic cloning and embryonic/adult stem cell therapy (reviewed in 2-5).
The role of embryonic stem cells in the treatment of pathophysiological disorders has recently attracted significant interest and has been the subject of much controversy. The pluripotency of embryonic stem cells presents the possibility of their use for replacement of damaged kidney tissue. First indications show that mouse embryonic stem cells, develop an endoderm-like tissue in culture and in kidney transplants [6]. However, the in vitro generation of mesodermal precursors that give rise to the adult kidney remains unsubstantiated.
Furthermore, the transplantation of ES cells includes potential complications of immune rejection, teratomas and other cancers [4, 7]. The problems associated with the use of embryonic stem cells and the potential benefit of autologous transplantation has spurred an intensive search for adult stem cell populations. It is increasingly clear that stem cells may originate not only from embryonic, but also from adult tissue, including adult brain, bone marrow, skin and gut, where they can be recruited for organ repair after injury [8, 9]. Until recently, adult stem cells in kidney had not been identified [2-4, 10]. Progenitor-like cells involved in recovery from renal injury in an animal model were first identified in 2003 [11], and in 2004 a population of rodent adult kidney stem cells derived from rat and mouse renal papilla was isolated and characterized [1]. Adult rodent renal stem cells were identified on the basis of their low cell division rate. To detect them, a pulse of bromodeoxyuridine (BrdU) was administered to rat and mouse pups, and after 2-months, a small population of BrdU-positive cells was detected in the renal papilla. These cells had a plastic phenotype and, following injection into the renal cortex, they incorporated into the parenchyma. Adult renal stem cells exhibited features characteristic of other stem cells and expressed both mesenchymal and epithelial proteins [1]. However, while rats and mice serve as important animal models for human physiology, one cannot necessarily predict from the results obtained in a rat or mouse model system that the same results will be obtained in a human system. For example, differing results may be obtained between an animal model, such as rat and mouse, and the human system because of differences in the immune systems, physiology, life spans, and/or hematopoetic pathways between humans and rodents.
Another potential source for endogenous replacement of damaged or lost renal tubular epithelia may be surviving tubular epithelial cells themselves. These cells have a capacity to adapt to the loss of neighboring cells through dedifferentiation and proliferation. Both glomerular and tubular epithelial cells can regress to an embryonic mesenchymal phenotype and can either stimulate a regenerative potential of neighboring surviving cells or replace the damaged cells [10, 11]. A functional role of these cells in organ repair is based on their ability to migrate, proliferate and produce growth and trophic factors.
Accordingly, there remain many open questions regarding the characteristics that define adult human renal stem cells, as well as their precise differentiation potential. However, the identification of adult human renal stem cells holds promise for numerous benefits including the development of renal tissue replacement strategies.